PREVENTING SKELETAL AND CARDIAC MUSCLE AGING BY RESTORING MITOCHONDRIAL FUNCTION SUMMARY Aging is accompanied by slowly progressive and irreversible structural changes and functional declines in both heart and skeletal muscle that combine to contribute to exercise intolerance and frailty in the elderly. The increased rates of nursing home placement and hospitalization make the loss of muscle function with age a growing public health crisis in terms of both quality of life and economic costs to society. Despite this, there are few treatment options to reverse either skeletal or cardiac muscle degeneration in the elderly, due in large part to the poor understanding of the mechanisms that underlie these dysfunctions. Our previous work has demonstrated that treatment with the mitochondrial targeted peptide SS-31 improves skeletal and cardiac muscle performance, mitochondrial function, and reduces redox stress. These surprising results demonstrate that mitochondrial dysfunction with age is a more dynamic process than previously thought and can be reversed by late-life treatment to improve healthspan. Recent data indicates that SS-31 does not act as a traditional antioxidant by scavenging reactive oxygen species. Instead SS-31 appears to interact with mitochondrial cardiolipin to improve mitochondrial electron transport system (ETS) function and reduce mitochondrial oxidative stress. We propose that improved ETS function with short-term treatment reduces redox and energy stress which improves function and stress response of the aged heart and skeletal muscle. With long-term treatment this improved stress signaling restores mitochondrial and tissue structure, leading to further improvements in muscle performance. This proposal will define the redox and energy dependent signaling mechanisms by which SS-31 treatment reverses cardiac and skeletal muscle energetic dysfunction at late age (Aim 1), as well as the mechanisms by which these changes subsequently rejuvenates cardiac and skeletal muscle structure to improve performance (Aim 2). The final Aim 3 will test whether reducing mitochondrial oxidative stress by treating mice beginning in middle age can preserve muscle healthspan and exercise tolerance. We believe that the combined study of both heart and skeletal muscle will provide key insights into similarities and differences in how their functional impairments respond to enhanced energetics and redox signaling and how improvements in both will combine to enhance healthspan and exercise tolerance. The end result will be new insights into the mechanistic basis of this new paradigm for improving muscle health with potential for direct translation to elderly humans.